The functional network of tumor necrosis factor (TNF) and TNF receptor superfamily members is composed of complex cross-talk between multiple ligands and multiple receptors, which regulate pleiotropic functions in the immune system (Aggarwal, Nat. Rev. Immunol., 3(9):745-56 (2003)). LIGHT, standing for homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes, is a type II transmembrane glycoprotein belonging to the TNF ligand superfamily (Mauri, et al., Immunity, 8(1):21-30 (1998)). LIGHT is expressed on immature dendritic cells (DCs) and activated T cells (Mauri, et al., Immunity, 8(1):21-30 (1998); Tamada, et al., J. Immunol., 164(8):4105-10 (2000)) and interacts with two functional receptors: lymphotoxin-β receptor (LTβR) and HVEM (Mauri, et al., Immunity, 8(1):21-30 (1998)). LIGHT interaction with LTβR triggers the production of proinflammatory mediators (Lee, et al., Arterioscler. Thromb. Vasc. Biol., 21(12):2004-10 (2001); Kim, et al., Immunology, 114(2):272-9 (2005)), up-regulates adhesion molecule expression (Yu, et al., Nat. Immunol., 5(2):141-9 (2004)), and induces apoptotic cell death in certain tumors (Rooney, et al., J. Biol. Chem., 275(19):14307-15 (2000)). On the other hand, by signaling through HVEM, LIGHT costimulates T-cell activation (Tamada, et al., Nat. Med., 6(3):283-9 (2000)). In vivo experiments demonstrated that transgenic expression of LIGHT leads to spontaneous progression of inflammatory autoimmunity such as Crohn's disease (Wang, et al., J. Clin. Invest., 108(12):1771-80 (2001); Shaikh, et al., J. Immunol., 167(11):6330-7 (2001); Wang, et al., J. Immunol., 174(12):8173-82 (2005)), while genetic disruption of LIGHT results in impaired T-cell activation, particularly in CD8+ T cells (Ye, et al., J. Exp. Med., 195:795-800 (2002); Tamada, et al., J. Immunol., 168:4832-4835 (2002); Scheu, et al., J. Exp. Med., 195:1613-1624 (2002); Liu, et al., Int. Immunol., 15:861-870 (2003)), and renders mice less vulnerable to pathogenic inflammation, as shown in acute hepatitis models (Anand, et al., J. Clin. Invest, 116:1045-1051 (2006)). Thus, LIGHT regulates multiple immune functions of innate and adaptive immunity through interactions with LTβR and HVEM.
There are reports demonstrating therapeutic effects of decoy proteins of LTβR in various immunologic diseases, including autoimmunity, inflammation, and transplantation (Gommerman, et al., Nat. Rev. Immunol., 3:642-655 (2003); Spahn, et al., Infect. Immun., 73:7077-7088 (2005)), indicating that decoy LTβR could be a potential biologic for clinical immunotherapy, analogous to a decoy form of TNF-receptor (Moreland, et al., N. Engl. J. Med., 337:141-147 (1997)). Prolonged administration of decoy LTβR, however, might become a double-edged sword since it abrogates the maintenance of DC and natural killer/natural killer T (NK/NKT) cells (Wu, et al., J. Exp. Med., 190:629-638 (1999); Iizuka, et al., Proc. Natl. Acad. Sci. U.S.A., 96:6336-6340 (1999)) and inhibits the microstructure formation of lymphoid organs (Mackay, et al., Eur. J. Immunol., 27:2033-2042 (1997)), thus disrupting immune homeostasis.
Graft-versus-host disease (GVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation. Posttransplantation administration of immunosuppressants prevails as the current therapeutic choice for GVHD, but this treatment results in systemic immunosuppression that often leads to opportunistic pathogen infections and leukemic relapse (Murphy, et al, Curr. Opin. Immunol., 11:509-515 (1999); Blazar, et al., Philos. Trans. R. Soc. Lond. B Biol. Sci., 360:1747-1767 (2005)). To overcome these issues, blockade of T-cell costimulatory signals is among the most sought after alternatives to immunosuppressants (Murphy, et al., Curr. Opin. Immunol., 11:509-515 (1999); Blazar, et al., Philos. Trans. R. Soc. Lond. B Biol. Sci., 360:1747-1767 (2005)). Previous findings have suggested a therapeutic potential of LIGHT costimulation, in which administration of LTβR-Ig, a decoy LTβR, inhibits alloreactive cytotoxic T lymphocyte (CTL) generation and prolongs the survival of GVHD mice (Tamada, et al., Nat. Med., 6:283-289 (2000)). Combined therapy of LTβR-Ig and anti-CD40 ligand monoclonal antibody (mAb) further protects the recipient mice from GVHD by rendering alloreactive donor CTL anergic (Tamada, et al., J. Clin. Invest., 109:549-557 (2002)). However, the actual contribution of the LIGHT-HVEM costimulatory system to these findings remains elusive due to the antihomeostatic effects of decoy LTβR. It is possible that changes of DC function or cellular structure in lymphoid tissues could affect the intensity of adaptive immune responses. Direct evidence indicating a pathogenic role of LIGHT-HVEM costimulation in GVHD has not been elucidated.
It would be advantageous to provide new compositions and methods for separating the therapeutic effects of decoy LTβR from the potential adverse effects. While decoy LTβR interferes with three molecular interactions—LTβ-LTβR, LIGHT-LTβR, and LIGHT-HVEM—the antihomeostatic effects are largely dependent on LTβ-LTβR functions since the corresponding phenotypes are observed in LTβ- or LTβR-KO mice but not in LIGHT-KO mice (Ye, et al., J. Exp. Med., 195:795-800 (2002); Tamada, et al., J. Immunol., 168:4832-4835 (2002); Scheu, et al., J. Exp. Med., 195:1613-1624 (2002); Liu, et al., Int. Immunol., 15:861-870 (2003); Kabashima, et al., Immunity, 22:439-450 (2005); Wu, et al., J. Immunol., 166:1684-1689 (2001); Alimzhanov, et al., Proc. Natl. Acad. Sci. U.S.A., 94:9302-9307 (1997); Futterer, et al., Immunity, 9:59-70 (1998)).
Therefore, it is an object of the invention to provide compositions and methods of use thereof that reduce inflammatory immune responses but do not significantly disrupt normal immune system homeostasis such as by interfering with the maintenance of DC and natural killer/natural killer T (NK/NKT) cells or by inhibiting the microstructure formation of lymphoid organs.
It is another object of the invention to provide compositions and methods of use thereof that inhibit or reduce T cell costimulatory signals.
It is another object of the invention to provide compositions and methods for the treatment of immunologic disorders, including inflammatory responses.
It is another object of the invention to provide compositions and methods for the treatment of autoimmune disorders.
It is still another object of the invention to provide compositions and methods for treatment of graft rejection and graft-versus-host disease.